Thinning of cervical nerve roots and peripheral nerves in ALS as measured by sonography

ObjectiveProgressive atrophy and loss of motor axons is a hallmark of amyotrophic lateral sclerosis (ALS). Limited sonographic data are available on potential detection of atrophy of peripheral nerves and nerve roots in ALS.MethodsPatients with either definite or probable ALS and control subjects underwent sonographic evaluation of the cervical roots (C5, C6, and C7) and peripheral nerves (median and ulnar nerves) on the right. These diameters and cross-sectional areas (C6, median, and ulnar nerves) were compared.ResultsThe diameters and cross-sectional areas were consistently smaller in ALS than in controls. No correlation was present between the sonographic parameters and the disease severity, disease duration, age, or gender. The overall sensitivity and specificity tended to be greater in the cervical nerve roots than in the peripheral nerves.ConclusionsThis study shows atrophy of cervical nerve roots and peripheral nerves in ALS detected by sonography. Cervical nerve roots might be more appropriate to detect motor axon loss than peripheral nerves.SignificanceSonographic evaluation of nerve roots and peripheral nerves may be a useful disease marker in ALS to confirm the diagnosis and to potentially monitor the disease progression.     

Swimming does not alter nociception threshold in obese rats submitted to median nerve compression

Objectives: We, herein, analyzed the effect of swimming on nociception threshold and peripheral nerve regeneration in lean and obese rats submitted to median nerve compression.

Methods: To induce obesity, newborn male Wistar rats received injections of monosodium glutamate (MSG), whereas the control (CTL) group received saline. The animals were separated into 6 groups; control and obese (CTL and MSG), control and obese with lesion (CTL LES and MSG LES), and control and obese with lesion submitted to physical exercise (CTL LES PE and MSG LES PE).

Results: Median nerve compression reduced nociception threshold in CTL LES and MSG LES rats. Swimming effectively altered nociception only in CTL LES PE animals. Lean and obese animals displayed histological differences, when compared to sedentary animals, and exercise improved axon regeneration in both groups. The brain-derived neurotrophic factor and GAP 43 protein expression was greater in animals submitted to nervous compression without alteration by exercise.

Discussion: In conclusion, swimming, a conservative treatment for peripheral nerve lesions, was not able to improve the nociception threshold in obese rats.     

Enhancement of synaptic strength in the somatosensory cortex following nerve injury does not parallel behavioural alterations

Following infraorbital nerve transection, underlying mechanisms of the altered synaptic strength were studied in rat barrel cortex slice experiments. In addition to the in vitro electrophysiological studies, open-field tests were run to detect possible behavioural changes associated with cortical oversensitization. Enhanced NMDA receptor-mediated component of the evoked field response appeared in the barrel cortex after nerve injury. The alteration was transient, very distinct on the first day following injury, and almost returned to normal level by the end of the second week. Behavioural changes had not followed this time-course since long-lasting alterations were detected in the open-field test. These observations are in agreement with findings that showed biphasic regenerative processes following nerve injuries in other cortical areas.     

Epidemiology of ALS in Padova district, Italy, from 1992 to 2005

Background and purpose:  Several studies have reported an increase in ALS incidence in recent years but population-based studies in Europe do not confirm this trend. To analyze ALS incidence over time we conducted a retrospective incidence study in the Padova district of Italy (1992 to 2005). We had previously conducted a survey in the same area in the years 1980–1991.
Methods:  We used the archives of all the neurological wards of the Padova district to identify all subjects with a discharge diagnosis of ALS or motor neuron disease and resident in the Padova district.
Results:  We ascertained 182 patients (85 males and 97 females; male:female ratio 0.88:1) over the 14-year study period. The annual incidence rates adjusted by sex and age increased from 1.31/100000/year in the years 1992–1994 to 1.92/100000/year in the years 2004–2005.
Conclusions:  This study confirmed an ALS incidence increase over the last 25 years in the Padova district. The increase in incidence may be partially explained by the ageing of the general population rather than by an improved diagnostic assessment.     

Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs), and is considered a potential agent for the treatment of amyotrophic lateral sclerosis (ALS) and other MN diseases. The effectiveness of GDNF may depend significantly upon its route of delivery to MNs. In this study we tested the neuroprotective effects of target-derived and centrally derived GDNF in the G93A-SOD1 mouse model of ALS using a transgenic approach. We found that overexpression of GDNF in the skeletal muscle (Myo-GDNF mice) significantly delayed the onset of disease and increased the life span of G93A-SOD1 mice by 17 days. The duration of disease also increased by 8.5 days, indicating that GDNF slowed down the progression of disease. Locomotor performance in Myo-GDNF/G93A-SOD1 mice was also significantly improved. The behavioral improvement correlated well with anatomical and histological data. We demonstrated that muscle-derived GDNF resulted in increased survival of spinal MNs, and twice as many MNs survived in end-stage double transgenic mice compared to end-stage G93A-SOD1 mice. Muscle-derived GDNF also had profound effects on muscle innervation and axonal degeneration. Significantly higher numbers of completely or partially innervated NMJs and large caliber myelinated axons were found in double transgenic mice. In contrast, we demonstrated that overexpression of GDNF in astrocytes in the CNS (GFAP-GDNF mice) failed to demonstrate any neuroprotective effects in G93A-SOD1 mice both on behavioral and histological levels. These data indicate that retrograde transport and signaling of GDNF is more physiological and effective for ALS treatment than anterogradely transported GDNF.     

Decreased brain activation to tongue movements in amyotrophic lateral sclerosis with bulbar involvement but not Kennedy syndrome

Neuroimaging studies in amyotrophic lateral sclerosis (ALS) investigating movements of the hands have in general found increased activation compared to healthy controls, which has been interpreted in terms of cortical adaptation as a result of corticospinal tract damage. Here, we investigated brain activations to vertical tongue movements using functional MRI at 3 tesla. Whereas healthy controls, patients with Kennedy syndrome, and ALS patients without bulbar involvement showed robust and indistinguishable activations in pre- and postcentral areas and the thalamus, ALS patients with bulbar involvement showed a significant decrease of cortical activity and missing thalamic activity. This decrease stands in marked contrast to the increase of activity observed in ALS patients when performing limb movements. We discuss these divergent findings with regard to the different physiological properties of tongue and limb movements. These findings may also help to explain the faster time-course of the disease in patients with bulbar involvement.     

The spectrum of Charcot-Marie-Tooth disease due to myelin protein zero: An electrodiagnostic,nerve ultrasound and histological study

Objective

Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology.

ALS in the Kii Peninsula of Japan,with Special Reference to Neurofibrillary Tangles and Aluminum

Epidemiological and environmental findings of the foci of amyotrophi lateral sclerosis (ALS) in the Western Pacific indicate a possible contributing role of metals, especially aluminum, in the pathogenesis. Al is also a candidate as a causative agent in the formation of neurofibrillary tangles (NFTs), which are characteristic of Guam ALS. To elucidate the pathogenesis of ALS, we conducted neuropathological examination and metal analysis, with special reference to NFT and Al in cases of ALS in the Kii Peninsula of Japan. We examined six of these ALS cases, ten ALS cases from non-focused areas (non-focused ALS) and eight disease controls. The neuropathologic characteristics of Kii ALS were the appearance of NFT in Ammon's horn, temporal cortex, mid-brain and pons, in ccombination with typical ALS pathology. No senile plaque was found in the Kii cases. Non-foused ALS patients rarely showed NFTs in Ammon's horn. Al analysis of Ammon's horns by particle-induced X-ray emission spectrometry (PIXE) revealed a high level of Al signals in the Kii cases, with positive correlation between Al content and NFT frequency. Kii ALS cases showed high level of Al signals in the cervical and lumbar spinal cords ccompared with non-foused ALS and controls. The Morin fluorescent technique revealed more conspicuous green fluorescence in the cytoplasm and nuclei of both the NFT-laden neurons and the degenerative neurons without NFT in Ammon's horn in the Kii ALS cases than in non-focused ALS cases. Green fluorescence was seen in a small number (2%) of the NFTs themselves. We suggest that Al induces abnormality in cytoskeletal protein such as neurofilaments and/or tau, and may cause the formation of NFT in Ammon's horn and also degeneration of motor neurons in Kii ALS.     

The Use of Telehealth to Enhance Care in ALS and other Neuromuscular Disorders

Telehealth has the potential to improve the efficiency of healthcare while reducing the burden on patients and caregivers. Encounters can be synchronous or asynchronous. When used for care of those with amyotrophic lateral sclerosis (ALS) by individual health care providers or by a multidisciplinary team, synchronous telehealth is feasible, acceptable, may produce outcomes comparable to those of in-person care, and is cost effective. Individuals with ALS who use telehealth tend to have lower physical and respiratory function and to live farther from an ALS clinic than those who exclusively attend in-person clinic visits. Asynchronous telehealth can be used as a substitute full multidisciplinary visits, or for remote monitoring of pulmonary function, gait/falls, and speech. Barriers to implementing telehealth on a wider scale include disparities in access to technology and challenges surrounding medical licensure and billing, but these are being addressed.     

Textural markers of ultrasonographic nerve alterations in amyotrophic lateral sclerosis

Ultrasound has revealed cross-sectional nerve area (CSA) reduction in amyotrophic lateral sclerosis (ALS), but little is known about the sonographic nerve texture beyond CSA alterations. In a large cohort of 177 ALS patients and 57 control subjects, we investigated the covariance and disease-specific signature of several sonographic texture features of the median and ulnar nerves and their relationship to the patients’ clinical characteristics. ALS patients showed atrophic nerves, a loss of the intranerve structures’ echoic contrast, elevated coarseness, and a trend toward lower cluster shading compared with controls. A reduction in intranerve echoic contrast was related to longer disease duration and poorer functional status in ALS. Sonographic texture markers point toward a significant reorganization of the deep nerve microstructure in ALS. Future studies will be needed to further substantiate the markers’ potential to assess peripheral nerve alterations in ALS.     

Diaphragm motor responses to phrenic nerve stimulation in ALS: Surface and needle recordings

Objective

In studies of phrenic nerve (PN) conduction in amyotrophic lateral sclerosis (ALS) both motor response amplitude and latency have been reported as abnormal. However, correlation with diaphragm motor unit loss, and with diaphragmatic function has not been fully evaluated.

Use of Bayesian MUNE to show differing rate of loss of motor units in subgroups of ALS

Objectives

To evaluate differences among patients with different clinical features of ALS, we used our Bayesian method of motor unit number estimation (MUNE).

Methods

We performed serial MUNE studies on 42 subjects who fulfilled the diagnostic criteria for ALS during the course of their illness. Subjects were classified into three subgroups according to whether they had typical ALS (with upper and lower motor neurone signs) or had predominantly upper motor neurone weakness with only minor LMN signs, or predominantly lower motor neurone weakness with only minor UMN signs. In all subjects we calculated the half life of MUs, defined as the expected time for the number of MUs to halve, in one or more of the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) muscles.

Results

The mean half life of MUs was less in subjects who had typical ALS with both upper and lower motor neurone signs than in those with predominantly upper motor neurone weakness or predominantly lower motor neurone weakness. In 18 subjects we analysed the estimated size of the MUs and demonstrated the appearance of large MUs in subjects with upper or lower motor neurone predominant weakness. We found that the appearance of large MUs was correlated with the half life of MUs.

Conclusions

Patients with different clinical features of ALS have different rates of loss and different sizes of MUs.

Significance

These findings could indicate differences in disease pathogenesis.     

Relationship of oxygen radical-induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS

Transgenic mice that overexpress a mutated human CuZn superoxide dismutase (SOD1) gene (gly⁹³→ala) found in some patients with familial ALS (FALS) have been shown to develop motor neuron disease, as evidenced by motor neuron loss in the lumbar and cervical spinal regions and a progressive loss of voluntary motor activity. The mutant Cu,Zn SOD exhibits essentially normal dismutase activity, but in addition, generates toxic oxygen radicals as a result of an enhancement of a normally minor peroxidase reaction. In view of the likelihood that the manifestation of motor neuron disease in the FALS transgenic mice involves an oxidative injury mechanism, the present study sought to examine the extent of lipid peroxidative damage in the spinal cords of the TgN(SOD1-G93A)G1H mice over their life span compared to nontransgenic littermates or transgenic mice that overexpress the wild-type human Cu,Zn SOD (TgN(SOD1)N29). Lipid peroxidation was investigated in terms of changes in vitamin E and malondialdehyde (MDA) levels measured by HPLC methods and by MDA-protein adduct immunoreactivity. Four ages were investigated: 30 days (pre-motor neuron pathology and clinical disease); 60 days (after initiation of pathology, but predisease); 100 days (approximately 50% loss of motor neurons and function); and 120 days (near complete hindlimb paralysis). Compared to nontransgenic mice, the TgN(SOD1-G93A)G1H mice showed blunted accumulation of spinal cord vitamin E and higher levels of MDA (P < 0.05 at 30 and 60 days) over the 30–120 day time span. In the TgN(SOD1)N29 mice, levels of MDA at age 120 days were significantly lower than in either the TgN(SOD1-G93A)G1H or nontransgenic mice. MDA-protein adduct immunoreactivity was also significantly increased in the lumbar spinal cord at age 30, 100, and 120 days, and in the cervical cord at 100 and 120 days. The results clearly demonstrate an increase in spinal cord lipid peroxidation in the FALS transgenic model, which precedes the onset of ultrastructural or clinical motor neuron disease. However, the greatest intensity of actual motor neuronal lipid peroxidative injury is associated with the active phase of disease progression. These findings further support a role of oxygen radical-mediated motor neuronal injury in the pathogenesis of FALS and the potential benefits of antioxidant therapy. J. Neurosci. Res. 53:66–77, 1998. © 1998 Wiley-Liss, Inc.     

Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS

Transgenic mice that highly over-express a mutated human CuZn superoxide dismutase (SOD1) gene [gly⁹³→ala; TgN(SOD1-G93A)G1H line] found in some patients with familial ALS (FALS) have been shown to develop motor neuron disease that is characterized by motor neuron loss in the lumbar and cervical spinal regions and a progressive loss of motor activity. The mutant Cu,Zn SOD exhibits essentially normal SOD activity but also generates toxic oxygen radicals as a result of an enhancement of a normally minor peroxidase reaction. Consequently, lipid and protein oxidative damage to the spinal motor neurons occurs and is associated with disease onset and progression. In the present study, we investigated the time course of microglial (major histocompatibility-II antigen immunoreactivity) and astrocytic (glial fibrillary acidic protein immunoreactivity) activation in relation to the course of motor neuron disease in the TgN(SOD1-G93A)G1H FALS mice. Four ages were investigated: 30 days (pre-motor neuron pathology and clinical disease); 60 days (after initiation of pathology, but pre-disease); 100 days (approximately 50% loss of motor neurons and function); and 120 days (near complete hindlimb paralysis). Compared to non-transgenic littermates, the TgN(SOD1-G93A)G1H mice showed significantly increased numbers of activated astrocytes (P < 0.01) at 100 days of age in both the cervical and lumbar spinal cord regions. However, at 120 days of age, the activation lost statistical significance. In contrast, microglial activation was significantly increased several-fold at both 100 and 120 days. We hypothesize that astrocytic activation may exert a trophic influence on the motor neurons that is insufficiently maintained late in the course of the disease. On the other hand, the sustained, intense microglial activation may conceivably contribute to the oxidative stress and damage involved in the disease process. If true, then agents which inhibit microglia may help to limit disease progression. GLIA 23:249–256, 1998. © 1998 Wiley-Liss, Inc.     

Exposure to nerve does not affect the appearance of calcium currents in embryonic muscle.

Xenopus skeletal muscle cells in culture develop two inward calcium currents, a slow and a transient current, which differ in terms of kinetics, voltage of activation and sensitivity to nifedipine. The slow current was present in many cells by the first day in culture and in all the cells by the second day in culture. In contrast, the transient current was present in only a small proportion of cells on the first day and in the majority of cells by the fifth day. We found that neither the characteristics of the two currents nor the developmental sequence of their appearance were altered by the presence or absence of nerve or by a prior exposure to nerve in-vivo.     

Increased expression of lipoprotein lipase in transgenic rabbits does not lead to abnormalities in skeletal and heart muscles

Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism and the uptake of free fatty acid in muscle. Previous studies using transgenic mice showed that increased LPL leads to myopathies, but these results were controversial. To examine this hypothesis, we studied LPL transgenic rabbits, and our results refute the suggested role of LPL in the pathogenesis of myopathies.